Rheumatoid arthritis is a chronic inflammatory disorder that afflicts at least 2.5 million Americans. This autoimmune disease is 2-3 times more common in women and typically affects the small joints in the hands and feet. Current therapeutic strategies include steroids and analgesics for the pain, while preventative strategies include disease modifying anti-rheumatic drugs (DMARDs). Unfortunately both steroids and DMARDs are not always effective, can result in serious toxicities, and are often costly. Thus, novel therapeutic approaches to rheumatoid arthritis, particularly cost-effective, steroid-sparing small molecule therapies, are in great demand. The broad long-term objective of this proposal is to advance a small molecule rheumatoid arthritis therapeutic into clinical service. This technology, being developed at the academic partner (The Feinstein Institute for Medical Research), targets macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine whose dysregulation underlies many autoimmune diseases. In addition to being the only cytokine that lends itself to small molecule intervention, MIF is known to counteract glucocorticoid action. Thus MIF intervention will be steroid-sparing. Feinstein and Biomedical Research Models, Inc. (BRM) - a small business with expertise in drug development testing and a particular emphasis in autoimmune models - now propose a joint venture to begin assessing the therapeutic efficacy of small molecule MIF inhibitors using BRM's validated preclinical models of rheumatoid arthritis. We will accomplish our goals by pursuing two Specific Aims: 1. Select a lead and back-up lead MIF inhibitor using established in vitro assays. Feinstein has developed five (5) proprietary MIF inhibitors which exhibit enhanced potency relative to a well- characterized positive control. Each of these drug candidates will be screened for their ability to inhibit (i) pro-inflammatory cytokine release from monocytes and (ii) the invasion of synovial fibroblast-like cells into a collagen matrix. 2. Perform dose efficacy studies on the lead and back-up lead in industry-accepted mouse and rat rheumatoid arthritis models. Following scale-up synthesis, these critical in vivo studies will be carried out at BRM. Dose finding studies and PK profiling will first be performed with a preference for oral dosing. An optimized dose and route of administration will then be chosen to test the therapeutic efficacy of two lead compounds in the RA models PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is one of the most common and costly of autoimmune diseases in humans. It affects ~ 1% of the US population and is predominant in females. This project will potentially improve clinical practice in the treatment of RA by advancing a novel cost-effective therapy.